This 30 year Program brings together 5 Projects and 3 Cores from 2 institutions and 4 labs to explore the physiologic and pathophysiologic roles and signaling of receptors and ligands related to corticotropin releasing factor (CRF), a peptide we chemically identified at the inception of the Program. CRF is the principal neuroregulator of the hypothalamic-pituitary-adrenal (HPA) axis and acts within the brain to integrate endocrine, autonomic and behavioral responses to stressors. Many disorders including anxiety, type 2 diabetes, obesity, drug addiction and depression are associated with perturbations of the HPA axis and changes in production or sensitivity to CRF. We have chemically and biologically characterized multiple components of this system including two receptor genes (CRFR1 and CRFR2), a CRF binding protein and three urocortins (Ucn 1, 2 and 3). CRF and Ucn 1 have high affinity for CRFR1; Ucn 1 has high affinity for both receptor types; Ucn 2 and 3 are highly selective for CRFR2. This program has developed and analyzed mouse mutants that are deficient in the receptors and the three Ucns revealing unexpected roles for these peptides in the CNS, endocrine and cardiovascular systems, skeletal muscle and gastrointestinal tract. We continue our focus on stress and several projects are now emphasizing metabolism, namely control of appetite and regulation of insulin secretion and sensitivity. The 3D structures of the major binding domains of CRF receptors bound to ligands have been solved by NMR and progress has been made towards solubilizing full-length receptors. New potent and selective peptide antagonists of CRFR1 and 2 have been developed and are being used to probe the physiologic significance and the pharmacologic promise of these important signaling systems. Each of the Projects in this Program tests hypotheses relating to CRF and Ucns, and have free access to reagents and models developed within the Program. The Program comprises: Proj 1, W Vale, Project Director (PD): CRF and urocortins and their receptors; Proj 2, J Rivier, PD: Pharmacology of neuroendocrine peptides; Proj 3, S Choe/R Riek, PDs: Structural studies of the interaction between CRF G-protein coupled receptors and their ligands; Proj 4, G Koob/E Zorrilla, PDs: Behavioral significance of neuroendocrine peptides; Proj 5, P Sawchenko, PD: Anatomy of neuroendocrine peptide pathways in the brain; Core A, W Vale, Core Director (CD): Administrative; Core B, K-F Lee/ Vale, CDs: Biology; Core C, J Rivier/W Fischer, CDs: Chemistry. Specifying the contributions of the CRF family of ligands and receptors to the maintenance of homeostasis and to stress-linked allostasis may improve our ability to manage diseases, including mood and metabolic disorders